This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the last 15 years, we have seen an increasing interest in understanding the role of the amygdala, a complex structure involved in a wide range of normal behavioral functions and psychiatric conditions. Damage to the temporal lobe, where the amygdala is located, results in profound changes in primordial behaviors (fear, feeding and sexuality). Several functional neuroimaging studies have explored the role that the amygdala plays in emotional processing and regulation and, more broadly, in human social behavior (reward, motivation and learning), building upon hypotheses of previous cytoarchitectural findings of post-mortem human and animal studies. However, the lack of knowledge of amygdala organization and its connections to other brain areas and the complexity of emotional functions measured by behavioral tasks limits our understanding and require further investigation in "in vivo" human subjects. In our preliminary data we have been able to reconstruct fibers connecting the seed region, amygdala, to the ipsilateral cortices (frontal, temporal, parietal, insular, occipital cortices). Interestingly, despite the fact that the targets regions are wide-ranging, we found that the amygdala connects to highly functionally specialized sub-domains of these cortices, salient to the emotional process and regulation. Additionally, reconstructing the fibers connecting the amygdala to subcortical nuclei (nucleus accumbens, basal ganglia, thalamus), we have been able to identify in human subjects whether the amygdala connects to the ipsilateral cortices directly or indirectly via amygdala-subcortical-cortical circuits, paralleling and going far beyond findings of histological markers in animal studies. Moreover, seeding from individual cortical surface provided us with the noteworthy advantage of taking into account the large intersubjective anatomical variability, minimizing false positive connections such as those crossing a gyrus near the seed/target location that occurs when geometrical or template-derived masks (MNI, Talairach, etc ) are employed. The scale of this project far outpaces our current ability to manage/process data. Our hardware, in fact, is unable to support these analyses. However, the speed at which we could complete our projects could be greatly improved with additional computational power and parallel processors. In the past year, we have been able to finalize the analyses of only 18 healthy subjects out of the 35 already collected. Furthermore, exploring the amygdala connectivity map in 50 healthy controls will be just a first stage of this project. In fact, neuroimaging data are currently being collected in 50 depressed bipolar, 50 remitted bipolar, and 50 depressed unipolar individuals (about 50 have already been collected and are waiting to be analyzed). Supported by our initial observation we hypothesize that our multimodal neuroimaging approach, if facilitated by adequate computational power, will consent the mapping of the normative amygdala connectivity in healthy individuals and, more broadly of the abnormal amygdala connectivity in affective disorders, in vivo. Hence, to test our hypothesis we propose the following specific aims. Specific Aim 1: To combine a high-resolution MPRAGE acquisition with a 68-directions diffusion-weighted imaging sequence in 50 living healthy subjects. In this aim we propose to map the amygdala anatomical connectivity for the first time in vivo. First (i) we will employ an automated reconstruction of the brain's cortical and subcortical volumes based on a processing stream, controlled by a shell script (recon-all), implemented in FREESURFER. Second, (ii) these cortical and subcortical masks, defined in individual anatomical space, will then serve as seed/target regions to run probabilistic tractography (bedpostx and probtrackx, implemented in FSL). Specific Aim 2: To identify potential neuroanatomical marker of affective disorders. In this aim we propose to compare the amygdala connectivity in 50 healthy individuals and in such a large and representative sample of the wide spectrum of mood disorders. The success of this project depends on the ability not only to address the research challenges just listed but also to implement research advances and high performance computing of direct utility to the neuroimaging research. This project is ambitious and computationally-demanding, but it will be a milestone in the literature of emotion by clarifying the amygdala connectivity map of the human brain, in a large sample of healthy individuals and affective disorders. Such neuro-anatomical evidence will serve as groundwork to develop modern and holistic theories of the functional role of the amygdala and subsequent development of more tuned behavioral fMRI tasks. Rate-limiting-steps: First (i), to automatically reconstruct brain's cortical and subcortical regions, recon_all (FREESURFER) takes about 2 [unreadable] days/subject. Second (ii), bedpostx (FSL), which stand for Bayesian Estimation of Diffusion Parameters Obtained using Sampling Techniques, runs Markov Chain Monte Carlo sampling to build up distributions on diffusion parameters at each voxel and requires about 3 days processing time/subject (64 slices). This script allows parallel jobs;indeed, each slice could be preprocessed independently. Third (iii), to reconstruct the 30 probability tracks that we are currently exploring and ultimately map the amygdala, probtackx (FSL) takes about 24 hours/subject. Again, each probability tracks could be preprocessed independently. Our recruitment rate is about 1 subject/week.